Natural products - small molecules biosynthesized primarily by microorganisms, fungi and invertebrates - are engendered with diverse chemical structures that give rise to a broad range of biological activities and account for the majority of currently used therapeutics. With an emphasis on marine invertebrates, we have identified several classes of novel marine natural products that potently inhibit tumor cell growth in vitro, and HIV-1 infection. By employing distinct but complementary HIV-1 assays, we demonstrated that mirabamides, glycosylated and halogenated depsipeptides, inhibit HIV-1 infection at the early stage of entry, and the activity profiles for the suite of depsipeptides provided new structure activity relationships for this class of compounds.